The neuropeptide slow transmitter PACAP (pituitary adenylate cyclase activating polypeptide) is released at synapses that transduce stress responses to the brain, and mediate homeostatic adjustments to stress by the organism. Allostatic responses to systemic and psychogenic stressors at multiple points in development and throughout the life span are implicated as causative factors in depression and post-traumatic stress disorder (PTSD). Stress response pathways (resilience responses) may also be required to ameliorate delayed neuronal death (DND) in trauamtic brain injury, long-term exposure to intense physical or psychological stimuli, or brain inflammation in chronic neurodegenerative disease. Understanding the cellular mechanisms of stress transduction is crucial to developing effective therapeutic interventions for these disorders. We have now shown that PACAP released at the adrenomedullary synapse and in the hypothalamus is required for stress hormone synthesis and full activation of the hypothalamic-pituitary-adrenocortical and hypothalamic-sympathoadrenomedullary axes during prolonged stress (Stroth and Eiden, Neuroscience 165:1025, 2010; Stroth et al., J. Neuroendocrinol. 23:944, 2011). In addition, PACAP-dependent activation of neuroprotective proteins accompanies prolonged stress at these anatomical locations, suggesting a second role for PACAP in limiting cellular damage accompanying overstimulation of stress-transducing cells. PACAP activates several genes in cultured bovine chromaffin cells which are also regulated by PACAP during stress in vivo, including those encoding steroidogenic and neuroprotective secreted peptides, such as galanin, stanniocalcin, and VIP. This induction is dependent on a novel cAMP-dependent, PKA-independent signaling pathway different from the one required for cAMP- and calcium-dependent effects on memory and learning. We have now characterized this signaling pathway so that pharmacological interventions in stress relevant to mental health might be developed that do not at the same time interfere with normal processes of memory and learning that depend on cyclic AMP. We have also characterized the induction of the neuro- and cardio-protective gene product stanniocalcin as a PACAP-regulated gene in a neuroblastoma-glioma cell line, and in cultured rat cortical neurons, and demonstrated that this pathway is also a cAMP-dependent, PKA-independent one (Holighaus, Mustafa and Eiden, Peptides 32:1647, 2011; Holighaus, Weihe and Eiden, J. Mol. Neurosci. 46:75, 2011). Recently, we have developed in collaboration with members of the Section on Functional Neuroanatomy, NIMH-IRP, behavioral assays for monitoring the role of PACAP in depressive behaviors generated by prolonged social stress. These studies suggest a role for PACAP in extrahypothalamic stress responses as well as in the regulation of the HPA axis. Thus, investigation of differential PACAP signaling in hypothalamus and limbic system relevant to stress management, versus PACAP signaling in cerebral cortex relevant to neuroprotection from the long-term effects of traumatic brain injury, is an urgent translational goal.